Many methods are now available to be used in the treatment of cancer. Despite considerable advances, however, treatments for many cancers are inadequate for a number of reasons.
There are still cancers which simply do not respond or respond poorly to treatments are currently available. Patients with treatable cancers must often undergo chemotherapy with drugs that cause severe side effects. Few of these drugs can be used orally. Perhaps the most serious problem associated with cancer chemotherapy is the development of multi-drug resistance by many tumors. For example, many tumors which initially respond positively to an anti-cancer therapy by decreasing in size or even going into remission often develop resistance to the drug. Tumors that have developed resistance to more than one drug are said to be a xe2x80x9cmulti-drug resistantxe2x80x9d. There is little that can be done to halt or retard further progression of the disease, once a patient""s cancer has become multi-drug resistant.
There is therefore still a need for new drugs which overcome one or more of the aforementioned shortcomings of drugs currently used in the treatment of cancer. Desirable properties of new anti-cancer drugs therefore include efficacy against tumors that are currently untreatable or poorly treatable, efficacy against multi-drug resistant tumors, oral bioavailability and/or reduced side effects.
It has now been found that certain 2-aroylimidazole compounds are cytotoxic against cancer cells, including multi-drug resistant cancer cells, from a number of different tissue types. For example, the IC50 of Compounds (1)-(12) against the multi-drug resistant human cancer cell line MES-SA/DX5 and HL-60/TX1000 was less than 0.5 xcexcM (see Examples 12-13 and 15). The structures of these compounds are shown in Example 11. In addition, the volume of tumors from the human breast cancer cell line MDA435 in nude mice was reduced by greater than 50% when Compound (2) was administered orally 
(Example 14). Little or no change in body weight was observed in mice treated with Compound (2), indicating that the compound caused minimal side-effects. Based on these results, novel 2-aroylimidazole compounds, pharmaceutical compositions comprising these 2-aroylimidazole compounds and methods of treating subjects with cancer by administering 2-aroylimidazole compounds are disclosed herein.
One embodiment of the present invention is a compound represented by Structural Formula (I): 
R1 is a substituted or unsubstituted 2-imidazolyl group which is optionally fused to a substituted or unsubstituted aryl group.
Z1 is xe2x95x90O, xe2x95x90S, xe2x95x90NOR11, or xe2x95x90NR11.
R is represented by a Structural Formula selected from (II)-(VII): 
Preferably, R is represented by Structural Formula (II) or (V).
Rings A-F are independently substituted or unsubstituted and are optionally fused to an aryl group.
R2 is xe2x80x94H, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group.
R3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted aliphatic group.
X is a covalent bond, xe2x80x94C(R4R5)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94 or xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94.
R4 and R5 are independently xe2x80x94H, an aliphatic group or a substituted aliphatic group.
R11 is xe2x80x94H or a substituted or unsubstituted alkyl group.
In one aspect, when R is represented by Structural Formula (II), then X is not xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 and R3 is not an aliphatic or substituted aliphatic group.
Another embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I). Preferably, the pharmaceutical composition comprises an effective amount of the compound. The pharmaceutical compositions can be used in therapy, e.g., as a treatment for cancer.
Another embodiment is a method of treating a subject with cancer. The method comprises administering to the subject an effective amount of a compound represented by Structural Formula (I).
Another embodiment is the use of a compound represented by Structural Formula (I) for the manufacture of a medicament for treating a subject with the cancer.
The disclosed compounds have many advantages when used to treat cancers. Most significantly, they are cytotoxic to many multi-drug resistant cell lines and therefore can be used when other traditional cancer chemotherapies have failed. In addition, they exhibit minimal side effects and are active when administered orally.